Apparatus and method for stimulation of biological tissue

ABSTRACT

An apparatus for generating focused currents in biological tissue is provided. The apparatus comprises an electric source capable of generating an electric field across a region of tissue and means for altering the permittivity of the tissue relative to the electric field, whereby a displacement current is generated. The means for altering the permittivity may be a chemical source, optical source, mechanical source, thermal source, or electromagnetic source.

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/814,843, filed on Jun. 19, 2006, the contents ofwhich being incorporated herein by reference in its entirety.

I. BACKGROUND OF THE INVENTION

A. Field of the Invention

The present invention relates generally to the field of alteringcurrents in the presence of an applied electric field or applied currentsource within biological material and more particularly to a method andapparatus to generate displacement currents in living tissue by alteringlocal tissue permittivity characteristics via mechanical, electrical,optical, chemical, and/or thermal means relative to an applied electricfield to stimulate biological tissue.

B. Background Information

Electric stimulation of living tissue in humans and other animals isused in a number of clinical applications as well as in clinical andgeneral biological research. In particular, electric stimulation ofneural tissue has been used in the treatment of various diseasesincluding Parkinson's disease, depression, and intractable pain. Focusedstimulation of the brain usually involves performing surgery to remove aportion of the skull and implanting electrodes in a specific locationwithin the brain tissue. The invasive nature of these procedures makesthem difficult and costly, and is responsible for a great deal ofmorbidity. Alternately, noninvasive stimulation methodologies such astranscranial direct current stimulation and transcranial magneticstimulation are easy to implement and are not associated withsignificant morbidity, however, the areas stimulated are large,typically not well characterized, and can be significantly perturbed bynatural or pathological features of the brain tissue. Recently,ultrasound stimulation of brain tissue has been explored with limitedsuccess.

Numerous methods exist for generating currents for biological tissuestimulation. These methods range from implanting electric sources in thetissue to inductively generating currents in tissue via time-varyingmagnetic fields. A common method for generating currents in tissues isto implant current sources within the tissue. Examples of this methodare illustrated, for example in U.S. Pat. No. 5,895,416 to Barreras, Sr.et al., U.S. Pat. No. 6,128,537 to Rise, U.S. Pat. No. 7,146,210 toPalti, and U.S. Pat. No. 6,091,992 to Bourgeois et al. Currents can alsobe produced in tissues with sources external to the tissues, such as viaexternal magnetic fields which induce currents in tissues. This methodis shown, for example, in U.S. Pat. No. 6,066,084 to Edrich et al., U.S.Pat. No. 5,061,234 to Chaney, U.S. Pat. No. 6,234,953 to Thomas et al.Another example is shown in U.S. Pat. No. 7,146,210 to Palti whichimplements electromagnetic radiation. Methods employing currentsproduced via electric sources placed in external contact to the tissuesuch that the currents attenuate through other tissues superficial tothe region of tissue to be stimulated are illustrated in U.S. Pat. No.4,989,605 to Rossen and U.S. Pat. No. 4,709,700 to Hyrman. None of thesetechniques generate currents via a permittivity perturbation in thepresence of an applied electric field. As such, these techniques sufferfrom limitations in the level of invasiveness, focality, penetration,and/or cost.

The concept of combining fields for the generation of altereddisplacement currents is relatively unexplored in the area of biologicaltissue stimulation. In the area of brain stimulation, magnetic fieldshave been explored with ultrasound techniques in the area of “halleffect stimulation,” for example, as in U.S. Pat. No. 5,476,438 Edrichet al., whereby “ionized particles within the nerve tissue and,particularly, electrons are mobilized” such that positive and negativeions are separated in the area of the orthogonal magnetic field wherethe ions are moving under the influence of ultrasound. This method doesnot attempt to generate a displacement current through the modificationof tissue permitivitties, but rather just local ionic separation viaapplying a magnetic field to moving ions. With the strength of magneticfields used in modern medical procedures, this technique is ineffectivefor stimulation. See Rutten, et al. (1996). Also in the area of brainstimulation, U.S. Pat. No. 6,520,903 to Yamashiro proposes a method toenhance energy transfer of magnetic fields by photonic fields focused onthe tissue, but it does not attempt to generate a displacement currentvia a tissue permittivity perturbation. Additionally, in the area ofbrain stimulation, U.S. Pat. No. 5,738,625 to Gluck (hereinafter“Gluck”) proposes the use of magnetic fields with a combined ultrasoundfield and/or microwave fields in order to change the membrane potentialof a neuron to a static value significantly different from the cell'sresting potential and a separate active depolarized state. Gluckproposes the modification of tissue conductivity via ultrasound suchthat currents induced by a magnetic field could flow on the paths ofaltered conductivity. Gluck also proposes the use of ultrasound to pushnerves in and out of the fields generated by the magnetic field. Gluckimplements a method altering which nerves are exposed to a magneticfield (or currents) and thus the magnetic based method of Gluck suffersfrom a loss in efficiency due to subsequent current attenuation.

Furthermore, Gluck proposes a method in which microwave and ultrasoundfields are combined in a way that may lead to non reversible changes tonerves. See Donald I. McRee, Howard Wachtel, Pulse Microwave Effects onNerve Vitality, Radiation Research, Vol. 91, No. 1 (July, 1982). Thepresent disclosure does not suffer from these safety concerns or causenerve damage by requiring the use of such high frequency electricfields. In addition, the disclosed invention herein is not constrainedto apply only to neural tissue exhibiting distinct states of quiescenceand activity, and would therefore be appropriate for dynamicallychanging action potentials that characterize almost all neural activityand for neurons with dynamic firing properties.

Other methods have been proposed for altering tissue conductivities foradapting current flow, such as U.S. Pat. No. 6,764,498 to Mische andU.S. Pat. No. 6,887,239 to Elstrom et al., but similarly, these methodsdo not provide a method that generates a new current component throughthe modification of the tissue electromagnetic properties.

Other studies have proposed techniques to affect neural stimulation withcombined fields but all suffer from inherent limitations in that thetechniques do not attempt to generate displacement currents forstimulation but attempt to affect stimulation through other means. SeeRutten, W. L. C., E. Droog et al.; The influence of ultrasound andultrasonic focusing on magnetic and electric peripheral nervestimulation, J. Nilsson, M. Panizza and F. Grandori; Pavia Advances inMagnetic Stimulation, Mathematical Modeling and Clinical Applications.,Italy. 2: 152. (1996) (hereinafter “Rutten”); Mihran, R. T., F. S.Barnes et al., Temporally-Specific Modification of Myelinated AxonExcitability in Vitro Following a Single Ultrasound Pulse. UltrasoundMed Biol 16(3): 297-309. (1990) (hereinafter “Mihran”); and Fry, W. J.,Electrical Stimulation of Brain Localized Without Probes—TheoreticalAnalysis of a Proposed Method, J Acoust Soc Am 44(4): 919-31. (1968)(hereinafter “Fry”).

Mihran and Rutten focus on altering ionic stretch receptors in neuralelements. Thus by not focusing on the generation of displacementcurrents through the appropriate combination of electric and mechanicalfields, these studies are limited in applicability and effectiveness.More specifically, the Mihran study combines ultrasound with electricalstimulation to test the effects of stretch receptors on nerves. Mihrandoes not attempt to generate new currents for stimulation. Mihranpurposely decouples the electric and mechanical fields. The primaryfocus of Rutten is to combine ultrasound and transcranial magneticstimulation (TMS), however, the study attempts electrical stimulationand ultrasound in an attempt to analyze the effects of stretch receptorssimilar to Mihran. Rutten does not attempt to combine the effects forthe generation of new current components or alter the appliedstimulatory currents in any way.

Fry presents an idea regarding how to generate a current modification inthe brain by modifying the tissue conductivity via ultrasound and thusdriving neural stimulation through a conductivity change alone. Fryproposes a theoretical, pseudo invasive, method based on the use ofultrasound and electrodes placed on the brain surface. The method isbased on the alteration of tissue conductivity via temperature/pressurechanges generated from ultrasound to alter currents generated by thebrain surface electrodes. The method has never been shown to work forneural stimulation, possibly because the theory is limited by manyconstraints. By focusing on modifying just the tissue conductivity toalter currents generated with higher frequency electric fields, thesource strengths required for stimulation are not trivial. Therefore,the method necessitates electrodes that must be placed on the exposedbrain surface, or much stronger current sources, which if placed on thescalp surface, would suffer from the limitations of TranscranialElctrostimulation (TES) and Electroconvulsive Therapy (ECT), i.e.,current strengths which activate pain receptors on the scalp surface orwith strengths necessary for stimulation that may potentially lead toscalp burns. And the ultrasound intensities that are necessary for thistheoretical stimulation are large enough in magnitude that concernsarise including temperature rise in the tissue, tissue cavitation, andthe possibility of tissue ablation. Thus, these safety limitations wouldpreclude one from applying this type of stimulation for any duration oftime, either with electrodes on the surface of the scalp or the brain.

The concept of mechanical and electric fields being interrelated inbiological tissues has been explored in the pursuit of imaging asillustrated in U.S. Pat. No. 6,645,144 to Wen, et al. and U.S. Pat. No.6,520,911 to Wen via electroacoustic, thermoacoustic, and Hall effects.These methods are focused on using one physical field to gleaninformation about the other and not in a combinatory way for biologicaltissue stimulation.

The prior art techniques do not attempt to generate capacitive currents,i.e., displacement currents, via a permittivity perturbation relative toan applied electric field for biological tissue stimulation. It is thusevident from the above that there is a need for an improved apparatusand method to generate displacement currents in living tissue byaltering local tissue permittivity characteristics via mechanical meansrelative to an applied electric field to stimulate biological tissue. Itis evident that there is a need for an improved method for stimulatingbiological tissue by altering local tissue permittivity that is lessinvasive and has improved focality. It is further evident that there isa need for an apparatus and method whereby actual currents are generatedas opposed to methods where the currents are altered in path or methodsaltering which nerves are exposed to a magnetic field. It is alsoevident that there is a need to generate currents below tissueboundaries without subsequent current attenuation and loss in efficiencyas takes place with magnetic and electrical based methods. It is evidentthat there is a need for a safe method that does not cause nerve ortissue damage by requiring the use of high frequency electromagneticfields, high intensity electromagnetic fields, and/or high intensityultrasound fields. It is also evident that there is a need for atolerable method that does not require field strengths that activatepain receptors during stimulation. Additionally, it is evident thatthere is a need for an apparatus and method that is not constrained toapply only to neural tissue exhibiting distinct states of quiescence andactivity, and would therefore be appropriate for dynamically changingaction potentials that characterize almost all neural activity and forneurons with dynamic firing properties.

II. SUMMARY OF THE INVENTION

Accordingly, an apparatus for generating currents in biological tissueis provided. The apparatus according to the disclosure includes anelectric source capable of generating an electric field across a regionof tissue and a means for altering the permittivity of tissue relativeto the electric field, whereby the alteration of the tissue permittivityrelative to the electric field generates a displacement current in thetissue. The means for altering the permittivity may include a chemicalsource, optical source, mechanical source, thermal source, orelectromagnetic source. In one embodiment, the apparatus implements anultrasound source as mechanical means for altering the permittivity ofthe tissues. In another embodiment the apparatus further includes ameans for altering the conductivity of tissue relative to the electricfield, whereby the ohmic current is altered.

In one exemplary embodiment, the apparatus includes an electric sourcecapable of generating an electric field across a broad region of tissueor tissues. The apparatus also includes an ultrasound device thatgenerates a mechanical field focused on the sub-region of tissue wherebythe combined effects of the electric field and the mechanical fieldgenerate an altered current with a newly generated displacement currentwithin the sub-region of tissue, via the alteration of tissueelectromagnetic properties.

The electric source according to the present disclosure may be appliedin a variety of ways to achieve a specified outcome. For example, theelectric source may generate a field that is pulsed, time varying, asequence of time varying pulses, or time invariant. Additionally, themeans for altering permittivity may be a pulsed signal, time varyingsignal, or a sequence of time varying pulse signals. The electric sourceand/or means for altering the tissue permittivity may be appliednon-invasively. For example, electrodes may be configured to be appliedto the specified tissue, tissues, or adjacent tissues. As onealternative, the electric source may be implanted inside the specifiedtissue, tissues, or adjacent tissues. Generally, the electric source iscurrent that has a frequency from about DC to approximately 100,000 Hz.

In one exemplary embodiment, the electric field is applied broadly andthe means is focused on a specific brain structure or multiplestructures for therapeutic purposes. The electric field may be appliedbroadly and the means may be focused on a structure or multiplestructures, such as brain or nervous tissues including dorsal lateralprefrontal cortex, any component of the basal ganglia, nucleusaccumbens, gastric nuclei, brainstem, thalamus, inferior colliculus,superior colliculus, periaqueductal gray, primary motor cortex,supplementary motor cortex, occipital lobe, Brodmann areas 1-48, primarysensory cortex, primary visual cortex, primary auditory cortex,amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontallobe, occipital lobe, temporal lobe, parietal lobe, sub-corticalstructures, peripheral nerves, and/or spinal cord.

The apparatus and method may assist in the treatment of a variety ofailments including Multiple Sclerosis, Amyotrophic Lateral Sclerosis,Alzheimer's Disease, Dystonia, Tics, Spinal Cord Injury, Traumatic BrainInjury, Drug Craving, Food Craving, Alcohol Craving, Nicotine Craving,Stuttering, Tinnitus, Spasticity, Parkinson's Disease, Parkinsonianism,Depression, Obsessions, Schizophrenia, Bipolar Disorder, Acute Mania,Catonia, Post-Traumatic Stress Disorder, Autism, Chronic Pain Syndrome,Phantom Limb Pain, Epilepsy, Stroke, Hallucinations, Movement Disorders,Neurodegenerative Disorders, Pain Disorders, Metabolic Disorders,Addictive Disorders, Psychiatric Disorders, Traumatic Nerve Injury, andSensory Disorders. Similarly, the electric field and the means foraltering permittivity may be focused on specific brain structures toenact procedures such as sensory augmentation, sensory alteration,anesthesia induction and maintenance, brain mapping, epileptic mapping,pre-surgical planning, neuroprosthetic interaction or control withnervous system, stroke and traumatic injury neurorehabilitation, bladdercontrol, assisting breathing, cardiac pacing, muscle stimulation, andtreatment of pain syndromes, such as those caused by migraine,neuropathies, and low-back pain; or internal visceral diseases, such aschronic pancreatitis or cancer.

In another embodiment, the apparatus according to the present disclosureincludes an electric source capable of generating an electric fieldacross a region of tissue and a means for altering the permittivity ofthe tissue relative to the electric field, whereby a displacementcurrent is generated. The apparatus further includes a means foraltering the conductivity of the tissue relative to the electric field,whereby the ohmic current is altered.

A method for stimulating biological tissue is also provided. The methodincludes applying an electric source to biological tissue and alteringthe permittivity of tissue relative to the electric source by applying ameans for altering the permittivity of tissue relative to the electricfield. The alteration of the permittivity of the tissue relative to theelectric field generates a displacement current in the tissue. The meansfor altering the permittivity may be a variety of sources including achemical source, optical source, mechanical source, thermal source, orelectromagnetic source. For example, a mechanical source such as anultrasound source may be applied to mechanically alter the tissue. Thetissue can be neural tissue, endocrine tissue, electrically receptivetissue, muscle tissue, connective tissue, or skeletal tissue. In afurther embodiment, the apparatus further includes a means for alteringthe conductivity of the tissue relative to the electric field, wherebythe ohmic current is altered.

III. BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned and other features and objects of this invention,and the manner of attaining them, will become more apparent and theinvention itself will be better understood by reference to the followingdescription of embodiments of the invention taken in conjunction withthe accompanying drawings, wherein:

FIG. 1 is a plan view of one embodiment of an apparatus for stimulatingbiological tissue constructed in accordance with the principles of thepresent disclosure;

FIG. 2 is a top plan view of an exemplary embodiment of an apparatus forstimulating biological tissue constructed in accordance with theprinciples of the present disclosure;

FIG. 3 is a top plan view of an exemplary embodiment of an apparatus forstimulating biological tissue implementing a chemical source foraltering permittivity constructed in accordance with the principles ofthe present disclosure;

FIG. 4 is a top plan view of an exemplary embodiment of an apparatus forstimulating biological tissue implementing a radiation source foraltering permittivity constructed in accordance with the principles ofthe present disclosure; and

FIG. 5 is a top plan view of another exemplary embodiment of anapparatus for stimulating biological tissue implementing an optical beamfor altering permittivity constructed in accordance with the principlesof the present disclosure.

IV. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

It is envisioned that the present disclosure may be used to stimulatebiological tissue in-vivo comprising an electric source that is placedon the body to generate an electric field and a means for altering thepermittivity of tissue relative to the electric field, whereby thealteration of the tissue permittivity relative to the electric fieldgenerates a displacement current in the tissue. The exemplaryembodiments of the apparatuses and methods disclosed can be employed inthe area of neural stimulation, where amplified, focused, directionaltered, and/or attenuated currents could be used to alter neuralactivity via directly stimulating neurons, depolarizing neurons,hyperpolarizing neurons, modifying neural membrane potentials, alteringthe level of neural cell excitability, and/or altering the likelihood ofa neural cell firing. Likewise, the method for stimulating biologicaltissue may also be employed in the area of muscular stimulation,including cardiac stimulation, where amplified, focused, directionaltered, and/or attenuated currents could be used to alter muscularactivity via direct stimulation, depolarizing muscle cells,hyperpolarizing muscle cells, modifying membrane potentials, alteringthe level of muscle cell excitability, and/or altering the likelihood ofcell firing. Similarly, it is envisioned that the present disclosure maybe employed in the area of cellular metabolism, physical therapy, drugdelivery, and gene therapy.

Detailed embodiments of the present disclosure are disclosed herein,however, it is to be understood that the described embodiments aremerely exemplary of the disclosure, which may be embodied in variousforms. Therefore, specific functional details disclosed herein are notto be interpreted as limiting, but merely as a basis for the claims andas a representative basis for teaching one skilled in the art tovariously employ the present disclosure in virtually any appropriatelydetailed embodiment.

The components of the tissue stimulation method according to the presentdisclosure are fabricated from materials suitable for a variety medicalapplications, such as, for example, polymerics, gels, films, and/ormetals, depending on the particular application and/or preference.Semi-rigid and rigid polymerics are contemplated for fabrication, aswell as resilient materials, such as molded medical grade polyurethane,as well as flexible or malleable materials. The motors, gearing,electronics, power components, electrodes, and transducers of the methodmay be fabricated from those suitable for a variety of medicalapplications. The method according to the present disclosure may alsoinclude circuit boards, circuitry, processor components, etc. forcomputerized control. One skilled in the art, however, will realize thatother materials and fabrication methods suitable for assembly andmanufacture, in accordance with the present disclosure, also would beappropriate.

The following discussion includes a description of the components andexemplary methods for generating currents in biological tissues inaccordance with the principles of the present disclosure. Alternateembodiments are also disclosed. Reference will now be made in detail tothe exemplary embodiments of the present disclosure illustrated in theaccompanying figures wherein like reference numerals indicate thesimilar parts throughout the figures.

Turning now to FIG. 1, which illustrates an exemplary embodiment of anapparatus 10 to alter currents, e.g., amplify, focus, alter direction,and/or attenuate in the presence of an applied electric field or appliedcurrent source by the combined application of a mechanical field withina biological material to stimulate the biological cells and/or tissue inaccordance with the present disclosure. For example, the apparatus 10illustrated in FIG. 1 according to the present disclosure may be appliedto the area of neural stimulation. An initial source electric field 14results in a current in the tissue. The electric field 14 is created byan electric source, current or voltage source. As described in furtherdetail below, the permittivity of the tissue is altered relative to theelectric field, for example by a mechanical field, thereby generating anadditional displacement current.

Electrodes 12 are applied to the scalp and generate a low magnitudeelectric field 14 over a large brain region. While electrodes 12 areused and applied to the scalp in this exemplary embodiment, it isenvisioned that the electrodes may be applied to a number of differentareas on the body including areas around the scalp. It is alsoenvisioned that one electrode may be placed proximal to the tissue beingstimulated and the other distant, such as one electrode on the scalp andone on the thorax. It is further envisioned that electric source couldbe mono-polar with just a single electrode, or multi-polar with multipleelectrodes. Similarly, the electric source may be applied to tissue viaany medically acceptable medium. It is also envisioned that means couldbe used where the electric source does not need to be in direct contactwith the tissue, such as for example, inductive magnetic sources wherethe entire tissue region is placed within a large solenoid generatingmagnetic fields or near a coil generating magnetic fields, where themagnetic fields induce electric currents in the tissue.

The electric source may be direct current (DC) or alternating current(AC) and may be applied inside or outside the tissue of interest.Additionally, the source may be time varying. Similarly, the source maybe pulsed and may be comprised of time varying pulse forms. The sourcemay be an impulse. Also, the source according to the present disclosuremay be intermittent.

A mechanical source such as an ultrasound source 16 is applied on thescalp and provides concentrated acoustic energy 18, i.e., mechanicalfield to a focused region of neural tissue, affecting a smaller numberof neurons 22 than affected by the electric field 14, by the mechanicalfield 18 altering the tissue permittivity relative to the appliedelectric field 14, and thereby generating the altered current 20. Themechanical source may be any acoustic source such as an ultrasounddevice. Generally, such device may be a device composed ofelectromechanical transducers capable of converting an electrical signalto mechanical energy such as those containing piezoelectric materials, adevice composed of electromechanical transducers capable of convertingan electrical signal to mechanical energy such as those in an acousticspeaker that implement electromagnets, a device in which the mechanicalsource is coupled to a separate mechanical apparatus that drives thesystem, or any similar device capable of converting chemical, plasma,electrical, nuclear, or thermal energy to mechanical energy andgenerating a mechanical field.

Furthermore, the mechanical field could be generated via an ultrasoundtransducer that could be used for imaging tissue. The mechanical fieldmay be coupled to tissue via a bridging medium, such as a container ofsaline to assist in the focusing or through gels and/or pastes whichalter the acoustic impedance between the mechanical source and thetissue. The mechanical field may be time varying, pulsed, an impulse, ormay be comprised of time varying pulse forms. It is envisioned that themechanical source may be applied inside or outside of the tissue ofinterest. There are no limitations as to the frequencies that can beapplied via the mechanical source, however, exemplary mechanical fieldfrequencies range from the sub kHZ to 1000 s of MHz. Additionally,multiple transducers providing multiple mechanical fields with similaror differing frequencies, and/or similar or different mechanical fieldwaveforms may be used—such as in an array of sources like those used infocused ultrasound arrays. Similarly, multiple varied electric fieldscould also be applied. The combined fields, electric and mechanical, maybe controlled intermittently to cause specific patterns of spikingactivity or alterations in neural excitability. For example, the devicemay produce a periodic signal at a fixed frequency, or high frequencysignals at a pulsed frequency to cause stimulation at pulse frequenciesshown to be effective in treating numerous pathologies. Such stimulationwaveforms may be those implemented in rapid or theta burst TMStreatments, deep brain stimulation treatments, epidural brainstimulation treatments, spinal cord stimulation treatments, or forperipheral electrical stimulation nerve treatments. The ultrasoundsource may be placed at any location relative to the electrodelocations, i.e., within, on top of, below, or outside the same locationas the electrodes as long as components of the electric field andmechanical field are in the same region. The locations of the sourcesshould be relative to each other such that the fields intersect relativeto the tissue and cells to be stimulated, or to direct the currentalteration relative to the cellular components being stimulated.

The apparatus and method according to the present disclosure generatescapacitive currents via permittivity alterations, which can besignificant in magnitude, especially in the presence of low frequencyapplied electric fields. Tissue permittivities in biological tissues aremuch higher than most other non biological materials, especially for lowfrequency applied electric fields where the penetration depths ofelectric fields are highest. This is because the permittivity isinversely related to the frequency of the applied electric field, suchthat the tissue permittivity magnitude is higher with lower frequencies.For example, for electric field frequencies below 100,000 Hz, braintissue has permittivity magnitudes as high as or greater than 10̂8(100,000,000) times the permittivity of free space (8.854*10̂-12 faradper meter), and as such, minimal local perturbations of the relativemagnitude can lead to significant displacement current generation. Asthe frequency of the electric field increases, the relative permittivitydecreases by orders of magnitude, dropping to magnitudes ofapproximately 10̂3 times the permittivity of free space (8.854*10̂-12farad per meter) for electric field frequencies of approximately 100,000Hz. Additionally, by not being constrained to higher electric fieldfrequencies, the method according to the present disclosure is anadvantageous method for stimulating biological tissue due to loweredpenetration depth limitations and thus lowered field strengthrequirements. Additionally, because displacement currents are generatedin the area of the permittivity change, focusing can be accomplished viathe ultrasound alone. For example, to generate capacitive currents via apermittivity perturbation relative to an applied electric field asdescribed above, broad DC or a low frequency electric source field wellbelow the cellular stimulation threshold is applied to a brain regionbut stimulation effects are locally focused in a smaller region byaltering the tissue permittivity in the focused region of a mechanicalfield generated by a mechanical source such as an ultrasound source.This could be done noninvasively with the electrodes and the ultrasounddevice both placed on the scalp surface such that the fields penetratethe tissue surrounding the brain region and intersect in the targetedbrain location, or with one or both of the electrodes and/or theultrasound device implanted below the scalp surface (in the brain or anyof the surrounding tissue) such that the fields intersect in thetargeted region.

A displacement current is generated by the modification of thepermittivity in the presence of the sub threshold electric field andprovides a stimulatory signal. In addition to the main permittivitychange that occurs in the tissues, which is responsible for stimulation(i.e., the generation of the altered currents for stimulation), aconductivity change could also occur in the tissue, which secondarilyalters the ohmic component of the currents. In a further embodiment, thedisplacement current generation and altered ohmic current components maycombine for stimulation. Generally, tissue conductivities vary slightlyas a function of the applied electric field frequency over the DC to100,000 Hz frequency range, but not to the same degree as thepermittivities, and increase with the increasing frequency of theapplied electric field. Additionally in biological tissues, unlike othermaterials, the conductivity and permittivity do not show a simpleone-to-one relationship as a function of the applied electric fieldfrequency. The permittivity ranges are as discussed above.

Although the process described may be accomplished at any frequency ofthe applied electric field, the method in an exemplary embodiment isapplied with lower frequency applied electric fields due to the fact thepermittivity magnitudes of tissues, as high as or greater than 10̂8 timesthe permittivity of free space, and the electric field penetrationdepths are highest for low frequency applied electric fields. Higherfrequency applied electric fields may be less desirable as they willrequire greater radiation power to penetrate the tissue and/or a morepronounced mechanical source for permittivity alteration to achieve thesame relative tissue permittivity change, i.e., at higher appliedelectric field frequencies the permittivity of the tissue is lower andas such would need a greater overall perturbation to have the sameoverall change in permittivity of a tissue as at a lower frequency.Applied electric field frequencies in the range of DC to approximately100,000 Hz frequencies are advantageous due to the high tissuepermittivity in this frequency band and the high penetration depth forbiological tissues at these frequencies. In this band, tissues arewithin the so called ‘alpha dispersion band’ where relative tissuepermittivity magnitudes are maximally elevated (i.e., as high as orgreater than 10̂8 times the permittivity of free space). Frequenciesabove approximately 100,000 to 1,000,000 Hz for the applied electricfields are still applicable for the method described in generatingdisplacement currents for the stimulation of biologic cells and tissue,however, both the tissue permittivity and penetration depth are limitedfor biological tissues in this band compared to the previous band butdisplacement currents of sufficient magnitude can still be generated forsome applications. In this range, the magnitude of the applied electricfield will likely need to be increased, or the method used to alter thepermittivity relative to the applied electric field increased to bringabout a greater permittivity change, relative to the tissue'spermittivity magnitude for the applied electric field frequency.Additionally, due to potential safety concerns for some applications, itmay be necessary to limit the time of application of the fields or topulse the fields, as opposed to the continuous application that ispossible in the prior band. For tissues or applications where the safetyconcerns preclude the technique in deeper tissues, the technique couldstill be applied in more superficial applications in a noninvasivemanner or via an invasive method. Higher frequency applied electricfields, above 1,000,000 to 100,000,000 Hz, could be used in generatingdisplacement currents for the stimulation of biologic cells and tissue.However, this would require a more sufficient permittivity alteration orelectromagnetic radiation, and as such is less than ideal in terms ofsafety than the earlier bands. For frequencies of the applied electricfield above 100,000,000 Hz, biologic cell and tissue stimulation maystill be possible, but may be limited for specialized applications thatrequire less significant displacement currents.

The focus of the electric and mechanical fields to generate an alteredcurrent according to the present disclosure may be directed to variousstructures within the brain or nervous system including but not limitedto dorsal lateral prefrontal cortex, any component of the basal ganglia,nucleus accumbens, gastric nuclei, brainstem, thalamus, inferiorcolliculus, superior colliculus, periaqueductal gray, primary motorcortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-48,primary sensory cortex, primary visual cortex, primary auditory cortex,amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontallobe, occipital lobe, temporal lobe, parietal lobe, sub-corticalstructures, spinal cord, nerve roots, sensory organs, and peripheralnerves.

The focused tissue may be selected such that a wide variety ofpathologies may be treated. Such pathologies that may be treated includebut are not limited to Multiple Sclerosis, Amyotrophic LateralSclerosis, Alzheimer's Disease, Dystonia, Tics, Spinal Cord Injury,Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol Craving,Nicotine Craving, Stuttering, Tinnitus, Spasticity, Parkinson's Disease,Parkinsonianism, Obsessions, Depression, Schizophrenia, BipolarDisorder, Acute Mania, Catonia, Post-Traumatic Stress Disorder, Autism,Chronic Pain Syndrome, Phantom Limb Pain, Epilepsy, Stroke, AuditoryHallucinations, Movement Disorders, Neurodegenerative Disorders, PainDisorders, Metabolic Disorders, Addictive Disorders, PsychiatricDisorders, Traumatic Nerve Injury, and Sensory Disorders. Furthermore,electric and mechanical fields to generate an altered current may befocused on specific brain or neural structures to enact proceduresincluding sensory augmentation, sensory alteration, anesthesia inductionand maintenance, brain mapping, epileptic mapping, neural atrophyreduction, neuroprosthetic interaction or control with nervous system,stroke and traumatic injury neurorehabilitation, bladder control,assisting breathing, cardiac pacing, muscle stimulation, and treatmentof pain syndromes, such as those caused by migraine, neuropathies, andlow-back pain; or internal visceral diseases, such as chronicpancreatitis or cancer.

In the focused region of tissue to which the mechanical fields aredelivered, the excitability of individual neurons can be heightened tothe point that the neurons can be stimulated by the combined fields, orbe affected such as to cause or amplify the alteration of the neuralexcitability caused by the altered currents, either through an increaseor decrease in the excitability of the neurons. This alteration ofneural excitability can last past the duration of stimulation and thusbe used as a basis to provide lasting treatment. Additionally, thecombined fields can be provided in multiple, but separate sessions tohave a summed, or carry-over effect, on the excitability of the cellsand tissue. The combined fields can be provided prior to another form ofstimulation, to prime the tissue making it more or less susceptible toalternate, follow-up forms of stimulation. Furthermore, the combinedfields can be provided after an alternate form of stimulation, where thealternate form of stimulation is used to prime the tissue to make itmore or less susceptible to the form of stimulation disclosed herein.Furthermore, the combined fields could be applied for a chronic periodof time.

FIG. 2 illustrates a set up 30 to perform a method for generating analtered current with a newly generated displacement current 32 forstimulation in biologic tissue 34 through the combined effects of anelectric field 36 and a mechanical field 38. A tissue or composite oftissues 34 is placed adjacent to the anode and cathode of an electricsource 40 which generates an electric field 36. The electric field 36 iscombined with a mechanical, e.g., ultrasound field 38 which can befocused on the tissue 34 and generated via an ultrasound transducer 42.In a sub-region of tissue 44 where the mechanical field 38 is focusedand intersects with the electric field 36, a displacement current 32 isgenerated. By vibrating and/or mechanically perturbing the sub-region oftissue 44, the permittivity of the tissue 44 can be altered relative tothe applied electric field 36 to generate a displacement current 32 inaddition to the current that would be present due to the source electricfield 36 and altered due to conductivity changes in the tissue caused bythe mechanical perturbation.

By providing the mechanical field 38 to the sub region of tissue 44, thepermittivity can be altered within the electric field 36 by either newelements of the sub region of tissue 44 vibrating in and out of theelectric field such that the continuum permittivity of the tissue ischanged relative to the electric field 36, or that the bulk propertiesof the sub region of tissue 44 and the permittivity, or tissuecapacitance, change due to the mechanical perturbation. An example ofaltering the permittivity within the electric field can occur when acell membrane and extra-cellular fluid, both of differentpermittivities, are altered in position relative to the electric fieldby the mechanical field. This movement of tissues of differentpermittivity relative to the electric field will generate a newdisplacement current. The tissues could have permittivity values as highas or greater than 10̂8 times the permittivity of free space, differ byorders of magnitude, and/or have anisotropic properties such that thetissue itself demonstrates a different permittivity magnitude dependingon the relative direction of the applied electric field. An example ofaltering permittivity of the bulk tissue occurs where the relativepermittivity constant of the bulk tissue is directly altered bymechanical perturbation in the presence of an electric field. Themechanical source, i.e., ultrasound source may be placed at any locationrelative to the electrode locations, i.e., within or outside the samelocation as the electrodes, as long as components of the electric fieldand mechanical field are in the same region.

Tissue permittivities can be altered relative to the applied electricfields via a number of methods. Mechanical techniques can be used toeither alter the bulk tissue permittivity relative to an appliedelectric field or move tissue components of differing permittivitiesrelative to an applied electric field. There are no specific limitationsto the frequency of the mechanical field that is applied as previouslydiscussed, however, exemplary frequencies range from the sub kHZ to 1000s of MHz. A second electromagnetic field could be applied to the tissue,at a different frequency than the initial frequency of the appliedelectromagnetic field, such that it alters the tissue permittivity atthe frequency dependent point of the initially applied electric field.An optical signal could also be focused on the tissues to alter thepermittivity of the tissue relative to an applied electric field. Achemical agent or thermal field could also be applied to the tissues toalter the permittivity of the tissue relative to an applied electricfield. These methods could also be used in combination to alter thetissue permittivity relative to an applied electric field via invasiveor noninvasive methods.

For example, FIG. 3 shows a set up 50 for generating an altered currentwith a newly generated displacement current 52 through the combinedeffects of an electric field 54 and a chemical agent 56. A tissue orcomposite of tissues 58 is placed within an electric source 60 whichgenerates an electric field 54 and combined with chemical source 62which releases a chemical agent 56 that can be focused on the tissue 58.In the area that the chemical agent 56 is released in the tissue 64, theelectric field 54 transects the sub region of tissue 64, and thechemical agent 56 reacts with the sub region of tissue 64 to alter thetissue's relative permittivity relative to the applied electric field54. This generates a displacement current 52 in addition to the currentthat would be present due to the source electric field 54. The chemicalagent 56 may be any agent which can react with the tissue or cellularcomponents of the tissue 64 to alter its permittivity relative to theelectric field 54. This may be by a thermoreactive process to raise orlower the tissue 64 temperature or through a chemical reaction whichalters the distribution of ions in the cellular and extra-cellularmedia, for instance, along ionic double layers at cell walls in thetissue 64. Similarly, the conformation of proteins and other chargedcomponents within the tissue 64 could be altered such that thepermittivity of the tissue is altered relative to the low frequencyelectric field 54. The agent could also be any agent that adapts thepermanent dipole moments of any molecules or compounds in the tissue 64,temporarily or permanently relative to the low frequency electric field54. The chemical reaction driven by the chemical agent 56 must workrapidly enough such that the permittivity of the tissue is quicklyaltered in the presence of the electric field 54 in order to generatethe displacement current 52. The reaction may also be such as tofluctuate the permittivity, such that as the permittivity continues tochange displacement currents continue to be generated. In addition tothe main permittivity change that occurs in the tissues, a conductivitychange could also occur in the tissue, which secondarily alters theohmic component of the currents. A biological agent may be used in placeof, or in addition to, the chemical agent 56. This embodiment may haveparticular application for focused drug delivery where an additionalchemical or biological agent is included to assist in therapy of thetissue, or where the altered current could drive an additionalelectrochemical reaction for therapy. For example, this could be used inareas such as focused gene therapy or focused chemotherapy.

Another example is shown in FIG. 4, which illustrates a set up 70 forapplying a method for generating an altered current with a newlygenerated displacement current 72 through the combined effects of a lowfrequency electric field 74 and an electromagnetic radiation field 76. Atissue or composite of tissues 78 is placed within a low frequencyelectric field 74 which is generated by an electric source 80 andcombined with radiation source 82 which generates a radiation field 76that can be focused on the tissue 78. In the area that the radiationfield 76 is focused in the tissue 78, the electric field 74 transectsthe sub component of tissue 84, where the radiation field 76 interactswith the sub component of tissue 84 to alter the tissue's relativepermittivity relative to the applied electric field 74, and as suchgenerates a displacement current 72 in addition to the current thatwould be present due to the source electric field 74 or the radiationsource field 76 alone. The electromagnetic radiation field 76 could, forexample, interact with the tissue 84 by altering its temperature throughohmic processes, alter the distribution of ions in the cellular andextra-cellular media for instance along ionic double layers along cellwalls through the electric forces acting on the ions, or alter theconformation of proteins and other charged components within the tissuethrough the electric forces such that the permittivity of the tissue isaltered relative to the low frequency electric field 74. Furthermore,the electromagnetic field 76, could interact with the tissue 84 bymoving components of the tissue via electrorestrictive forces, as wouldbe seen in anisotropic tissues, to alter the continuum permittivity ofthe tissue relative to the low frequency electric field 74. In additionto the main permittivity change that occurs in the tissues, aconductivity change could also occur in the tissue, which secondarilyalters the ohmic component of the currents.

FIG. 5 shows a set up 90 for applying a method for generating an alteredcurrent with a newly generated displacement current 92 through thecombined effects of an electric field 94 and an optical beam 96. Atissue or composite of tissues 98 is placed within electric field 94generated by an electric source 100 and combined with optical source 102which generates optical beam 96 that can be focused on the tissue 98. Inthe area that the optical beam 96 is focused on the tissue, the electricfield 94 transects the sub component of tissue 104, where the opticalbeam 96 reacts with the tissue to alter the tissue's relativepermittivity relative to the applied electric field 94, and as suchgenerates a displacement current 92 in addition to the current thatwould be present due to the source electric field 94. The optical beam96 could, for example, interact with the tissue by altering itstemperature through photothermal effects and/or particle excitation,alter the distribution of ions in the cellular and extra-cellular mediafor instance along ionic double layers along cell walls by exciting themovement of ions optically, ionizing the tissue via lasertissue-interactions, or alter the conformation of proteins and othercharged components within the tissue such that the permittivity of thetissue is altered relative to the low frequency electric field 94. Inaddition to the main permittivity change that occurs in the tissues, aconductivity change could also occur in the tissue, which secondarilyalters the ohmic component of the currents.

In another embodiment, a thermal source to alter the permittivity of thetissue may be used. In such embodiments, a thermal source such as aheating probe, a cooling probe, or a hybrid probe may be placed externalor internal to the tissue to be stimulated. A thermal source may alterthe permittivity of the tissue through the direct permittivitydependence of tissue temperature, mechanical expansion of tissues inresponse to temperature changes, or by mechanical forces that arise dueto altered particle and ionic agitation in response to the temperaturealteration such that permittivity of the tissue is altered relative toan applied electric field. In addition to the main permittivity changethat occurs in the tissues, a conductivity change could also occur inthe tissue, which secondarily alters the ohmic component of thecurrents. This embodiment may be useful for stimulation in the presenceof an acute injury to the tissue where the thermal source could be usedto additionally assist in the treatment of the tissue injury, forexample with a traumatic brain injury or an infarct in any organ such asthe heart. The tissue could be cooled or heated at the same timestimulation is provided to reduce the impact of an injury.

In a further embodiment, the method according to the present disclosureis applied in the area of muscular stimulation, where amplified,focused, direction altered, and/or attenuated currents could be used toalter muscular activity via direct stimulation, depolarizing muscularcells, hyperpolarizing muscular cells, modifying membrane potentials,and/or increasing or decreasing the excitability of the muscle cells.This alteration of excitability or firing patterns can last past theduration of stimulation and thus be used as a basis to provide lastingtreatment. Additionally, the stimulation can be provided in multiple,but separate sessions to have a summed, or carry-over effect, on theexcitability of cells and tissue. Additionally, the stimulation could beprovided to prime the tissue by adjusting the muscle cell excitabilityto make it more or less susceptible to alternate follow up forms ofstimulation. The stimulation could be used after another form ofstimulation was used to prime the tissue. Furthermore, the stimulationcould be applied for a chronic period of time. This embodiment may beuseful for altering or assisting cardiac pacing or function, assistedbreathing, muscle stimulation for rehabilitation, muscle stimulation inthe presence of nerve or spinal cord injury to prevent atrophy or assistin movement, or as substitution for physical exercise.

In yet another embodiment, the method according to the presentdisclosure can be applied the area of physical therapy, where amplified,focused, direction altered, and/or attenuated currents could be used tostimulate blood flow, increase or alter neuromuscular response, limitinflammation, speed the break down of scar tissue, and speedrehabilitation by applying the focus of the current generation to theeffected region in need of physical therapy. It is envisioned that themethod according to the present disclosure may have a wide variety inthe area of physical therapy including the treatment or rehabilitationof traumatic injuries, sports injuries, surgical rehabilitation,occupational therapy, and assisted rehabilitation following neural ormuscular injury. For instance, following an injury to a joint or muscle,there is often increased inflammation and scar tissue in the region anddecreased neural and muscular response. Typically, ultrasound isprovided to the affected region to increase blood flow to the region andincrease the metabolic re-absorption of the scar tissue while electricalstimulation is provided separately to the nerves and muscles; however,by providing them together, a person could receive the benefit of eachindividual effect, but additionally amplified stimulatory and metaboliceffects through the altered currents. The other methods for generatingaltered currents discussed within could also be used to assist inphysical therapy via the displacement currents that are generated.

Furthermore, the method according to the present disclosure may beapplied to the area of cellular metabolism, where currents could be usedto interact with electrically receptive cells or charged membranes toalter the tissue or cellular dynamics. It is envisioned that thisembodiment could provide treatment for various diseases whereelectrically receptive cells respond to the newly generated displacementcurrents and altered current distribution.

Furthermore, the method according to the present disclosure may beapplied to the area of gene therapy. Amplified, focused, directionaltered, and/or attenuated currents could be used to interact withelectrically receptive cells or receptors within the cell to influenceprotein transcription processes and alter the genetic content of thecells. The altered current densities in the tissue can interact with thetissue to stimulate this altered gene regulation. Additionally, thedisplacement currents generated by the method could further be used toassist in drug delivery and/or gene therapy through the altered currentinfluence on the delivery of agents.

While the inventions have been illustrated and described in detail inthe drawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatembodiments have been shown and described and that all changes andmodifications that come within the spirit of these inventions aredesired to be protected.

1-55. (canceled)
 56. A method for treating an ailment associated with aninjury to a joint, the method comprising: non-invasively providingstimulation transcranially to a subject's brain to treat an ailmentassociated with an injury to a joint, wherein the stimulation isprovided in a manner such that neural function is altered past durationof the stimulation, thereby treating the ailment associated with theinjury to the joint.
 57. The method according to claim 56, whereinstimulation is provide to one or more structures in the brain selectedfrom the group consisting of: dorsal lateral prefrontal cortex, anycomponent of the basal ganglia, nucleus accumbens, gastric nuclei,brainstem, thalamus, inferior colliculus, superior colliculus,periaqueductal gray, primary motor cortex, supplementary motor cortex,occipital lobe, Brodmann areas 56-48, primary sensory cortex, primaryvisual cortex, primary auditory cortex, amygdala, hippocampus, cochlea,cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe,parietal lobe, and sub-cortical structures.
 58. The method according toclaim 56, wherein the stimulation comprises at least two different typesof energy.
 59. The method according to claim 58, wherein a first type ofenergy is selected from the group consisting of: thermal, optical,mechanical, electromagnetic, and electrical.
 60. The method according toclaim 58, wherein a second type of energy is selected from the groupconsisting of: thermal, optical, mechanical, electromagnetic, andelectrical.
 61. The method according to claim 58, wherein the first typeof energy is an electric field.
 62. The method according to claim 61,wherein the electric field is pulsed.
 63. The method according to claim61, wherein the electric field is time varying.
 64. The method accordingto claim 61, wherein the electric field is pulsed a plurality of times,and each pulse may be for a different length of time.
 65. The methodaccording to claim 61, wherein the electric field is time invariant. 66.The method according to claim 61, wherein the second type of energy is amechanical field.
 67. The method according to claim 66, wherein themechanical field is generated by an ultrasound device.
 68. The methodaccording to claim 66, wherein the mechanical field is pulsed.
 69. Themethod according to claim 66, wherein the mechanical field is timevarying.
 70. The method according to claim 66, wherein the mechanicalfield is pulsed a plurality of times, and each pulse may be for adifferent length of time.